Cocaine addiction remains a major public health concern. Effective behavioral therapies for addiction such as cognitive behavioral therapy (CBT) target the extinction of learned drug associations in attaining their relapse prevention goals but have limited efficacy associated with high rates of recidivism. A proposed clinical drug trial supported by functional magnetic resonance imaging (fMRI) studies would test a working hypothesis that enhancing glutamate neurotransmission with the cognitive enhancer D-cycloserine (DCS) facilitates CBT-related relapse prevention by potentiating the behavioral and neural representation of the extinction of cocaine cue responses. Aim 1 of the proposed exploratory/developmental research plan would use a placebo-controlled, double-blind clinical trial design to determine if the short-term oral administration of DCS significantly enhances the relapse prevention, functional recovery, treatment retention, and cocaine craving reduction goals of an extinction-based CBT. Sixty cocaine-dependent men enrolled in a 4-week outpatient substance abuse treatment program (SATP) would be randomized to three treatment arms of the study (treatment as usual, CBT/placebo or CBT/DCS). A hypothesis that DCS represents a useful adjunct to CBT in producing a significant and durable enhancement of relapse prevention would be tested. Aim 2 would use behavioral, skin conductance, and fMRI response to Stroop tasks to define differences between the DCS and placebo groups in the rate and extent of extinction of the attentional bias for drug use reminders. This aim would test the specific hypothesis that DCS administration potentiates a CBT-related extinction of prior cocaine contingencies by enhancing the neural representation of extinction learning and memory. Aim 3 would use an exploratory pharmacogenetic imaging analysis to assess the influence of allelic variation for common haplotypes of genes involved in endocannabinoid signaling that regulate extinction processes on the impact of DCS on the clinical and neural response to CBT. The long term goal of the proposed translational research plan is to develop significantly more effective treatment plans promoting relapse prevention and recovery for cocaine, and perhaps other, addictions. PUBLIC HEALTH RELEVANCE: The proposed R21 would determine whether administration of the cognitive enhancer D-cycloserine (DCS) potentiates the relapse prevention and recovery goals of cognitive behavioral therapy in men and women with cocaine addiction. Longitudinal fMRI studies and the influence of sequence variation in endocannabinoid system genes would assess the role of extinction learning and memory in CBT-related and DCS-facilitated relapse prevention and the role of variation in extinction-related genes in interindividual differences in treatment response, respectively.